Imidazo[1,5]naphthyridine compounds, their pharmaceutical use and compositions   

This application is a 371 application of PCT/IB2009/054103, filed on Sep. 18, 2009, which claims the benefit of U.S. Provisional Application No. 61/101,564 filed on Sep. 30, 2008, and U.S. Provisional Application No. 61/187,077 filed on Jun. 15, 2009, the contents of which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to novel imidazo[1,5]naphthyridine compounds including their pharmaceutically acceptable salts as modulators or inhibitors of the phosphoinositide 3-kinase alpha (PI3-Kα) enzyme and/or PI3-Kα/mammalian target of rapamycin protein kinase (mTOR) dual inhibitors. The invention also relates to processes for the preparation of, intermediates used in the preparation of, pharmaceutical compositions containing and the uses of such compounds in treating diseases or conditions mediated by PI3-Kα and/or PI3-Kα/mTOR, such as for example, disease states associated with abnormal cell growth such as cancer.

BACKGROUND OF THE INVENTION

Activation of the PI3K pathway is a frequent event in human tumors, promoting cell proliferation, survival, and resistance to chemotherapy and radiotherapy. (Shaw et al. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature. 441 (2006), pp. 424-430; Verheijen et al. Phosphatidylinositol 3-kinase (PI3K) inhibitors as anticancer drugs. Drugs of the Future, 32 (2007), pp. 537-547.) Phosphoinositide 3-kinases (PI3-Ks) and mammalian target of rapamycin protein kinase (mTOR) are the key kinases in the PI3K signaling pathway.

PI3-Ks catalyze the synthesis of the phosphatidylinositol (PI) second messengers PI(3)P, PI(3,4)P2, and PI(3,4,5)P3 (PIP3). (Fruman et al., Phosphoinositide kinases, Annu. Rev. Biochem. 67 (1998), pp. 481-507; Knight et al., A Pharmacological Map of the PI3-K Family Defines a Role for p110α in Insulin Signaling, Cell 125 (2006), pp. 733-747.) In the appropriate cellular context, these three lipids control diverse physiological processes including cell growth, survival, differentiation, and chemotaxis. (Katso et al., Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer, Annu. Rev. Cell Dev. Biol. 17 (2001), pp. 615-675.) The PI3-K family comprises at least 15 different enzymes, sub-classified by structural homology, with distinct substrate specificities, expression patterns, and modes of regulation. The main PI3-kinase isoform in cancer is the Class I PI3-Kα, consisting of catalytic (p110α) and adapter (p85) subunits. (Stirdivant et al., Cloning and mutagenesis of the p110α subunit of human phosphoinositide 3′-hydroxykinase, Bioorg. Med. Chem. 5 (1997), pp. 65-74.) The 3-phosphorylated phospholipids (PIP3s) generated by PI3-Ks act as second messengers recruiting kinases with lipid binding domains (including plekstrin homology (PH) regions), such as AKT and phosphoinositide-dependent kinase-1 (PDK1). (Vivanco & Sawyers, The Phosphatidylinositol 3-Kinase—AKT Pathway In Human Cancer, Nature Reviews Cancer 2 (2002), pp. 489-501.) Binding of AKT to membrane PIP3s causes the translocation of AKT to the plasma membrane, bringing AKT into contact with PDK1, which is responsible for activating AKT. The tumor-suppressor phosphatase, PTEN, dephosphorylates PIP3 and therefore acts as a negative regulator of AKT activation. Functional loss of PTEN (the most commonly mutated tumour-suppressor gene in cancer after p53), oncogenic mutations in the PIK3CA gene encoding PI3-Kα, amplification of the PIK3CA gene and overexpression of AKT have been established in many malignancies. (see, for example, Samuels, et al., High frequency of mutations of the PIK3CA gene in human cancers, Science 304 (2004), p. 554; Broderick et al., Mutations in PIK3CA in anaplastic oligodendrogliomas, high-grade astrocytomas, and medulloblastomas, Cancer Research 64 (2004), pp. 5048-5050.) PI3-Kα is thus an attractive target for cancer drug development since such agents would be expected to inhibit proliferation and surmount resistance to cytotoxic agents in cancer cells.

mTOR is a serine/threonine kinase that controls the protein translation machinery and hence cell proliferation. (Faivre et al. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Disc. 5 (2006), pp. 671-688; Rosner et al. The mTOR pathway and its role in human genetic disease. Mutation Research 3 (2008), pp. 284-292; Hall and Schmelzle Cell, TOR, a central controller of cell growth. Cell 103 (2000), pp 253-252.) mTOR is active in two complexes: mTORC1, which is sensitive to inhibition by the immune suppressant rapamycin, and mTORC2, which is not inhibited by rapamycin. (Sabatini et al. RAFT1 a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORS. Cell 78 (1994), pp. 35-43); Sarbassov et al. Rictor, a novel binding partener of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol. 14 (2004), pp. 1296-1302.) The protein kinase activities of the two mTOR complexes can be regulated by signaling from growth factor receptors, via PI3K, or by the level of nutrients, particularly amino acids, available to the cell. In both cases mTOR regulation involves a protein complex comprised of TSC1 and TSC2. During growth factor signaling, RTKs activate PI3K, which in turn activates the protein kinases AKT and PDK1, via formation of PIP3. AKT can directly phosphorylate TSC2, which leads to inhibition of the GAP activity of the TSC1/TSC2 complex towards the GTPase Rheb. This in turn leads to activation of Rheb, which is thought to directly activate mTOR. The TSC1/TSC2 complex can also be regulated by PI3K-independent signals. Activation of the AMPK kinase in response to energy deprivation, such as low glucose or amino acids, leads to activation of the TSC1/TSC2 complex and downregulation of mTOR. Similar mechanisms account for suppression of mTOR by hypoxia and Wnt signaling. TSC1/TSC2 therefore serves as a point of integration of diverse cellular signals converging on mTOR regulation. Once activated, the mTORC1 complex phosphorylates two key substrates, 4EBP1 and S6 kinase. Phosphorylated 4EBP1 binds to ribosomal initiation factors and activated S6 kinase phosphorylates the ribosomal protein S6. The net result is the stimulation of cap-dependent translation and the synthesis of proteins that are required for entry into the DNA synthesis phase of the cell cycle. mTORC1 is therefore seen as a gatekeeper of cell cycle progression, integrating extracellular growth signals and energy status to decide whether the cell has an appropriate environment for proliferation. The mTORC2 complex does not regulate translation, but activates AKT by phosphorylation, leading to further mTOR activation as well as substrates such as BAD and FOXO that stimulate cell survival. mTOR-activated proteins promote several hallmarks of cancer such as cell growth and proliferation, angiogenesis, and bioenergetics. Since mTOR acts as a neoplastic switch that is frequently turned on by many mutations found in cancer, inhibition of mTOR offers a promising strategy for cancer therapy. Given that the mTOR pathway is deregulated in a number of cancers, it is anticipated that mTOR inhibitors will have broad therapeutic application across many tumor types.

Hence, in some tumors, targeting both PI3-Kα and mTOR may provide additional benefit compared with selectively targeting PI3-Kα. There is a need to provide new PI3-Kα inhibitors and/or dual PI3-Kα/mTOR inhibitors that are good drug candidates. They should be bioavailable, be metabolically stable and possess favorable pharmacokinetic properties.

SUMMARY

The present invention relates to novel compounds of Formula (I)

or a salt thereof,

wherein:

R1 is H, (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C6 to C14) aryl, (C2 to C9) cycloheteroalkyl, or (C2 to C9) heteroaryl, wherein said (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C6 to C14) aryl, (C2 to C9) cycloheteroalkyl, or (C2 to C9) heteroaryl is optionally substituted with at least one R6 group;

R2 is H, —(CH2)nC(O)OR7, —(CH2)nC(O)N(R8aR8b), (C1 to C6) alkyl, (C3 to Ca) cycloalkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C6 to C14) aryl, (C2 to C9) cycloheteroalkyl, or (C2 to C9) heteroaryl wherein the said (C1 to C6) alkyl, (C3 to Ca) cycloalkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C6 to C14) aryl, (C2 to C9) cycloheteroalkyl or (C2 to C9) heteroaryl is optionally substituted with at least one R6 group;

R3 is H or (C1 to C3) alkyl;

R and R4 are independently H, halo, cyano or (C1 to C6) alkyl;

R5 is H or (C1 to C6) alkyl wherein the said (C1 to C6) alkyl is optionally substituted with at least one R6 group;

each R6 is independently —OH, halogen, CF3, —(CH2)nNR8aR8b, (C1 to C6) alkyl, (C1 to C6) alkenyl, (C1 to C6) alkynyl, (C1 to C6) alkoxy, cyano, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, (C2 to C9) heteroaryl, —(CH2)nC(O)R9, —(CH2)nS(O)mR9, —(CH2)nS(O)mNR8aR8b, —(CH2)nNR8aS(O)mR9, —(CH2)nC(O)OR7, —(CH2)nC(O)NR8aR8b, —(CH2)nOC(O)R9, —(CH2)nNR8aC(O)R9 or —(CH2)nNR8aC(O)NR8aR8b, wherein each of the said (C1 to C6) alkyl, (C1 to C6) alkenyl, (C1 to C6) alkynyl, (C1 to C6) alkoxy, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, or (C2 to C9) heteroaryl is optionally substituted with at least one R10 group;

each R7 is independently H, or (C1 to C6) alkyl optionally substituted with at least one R10 group;

R8a and R8b are each independently H, (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl wherein each of the said (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl is optionally substituted with at least one R10 group;

each R9 is independently (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl wherein each of the said (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl is optionally substituted with at least one R10 group;

each R10 is independently —OH, halogen, CF3, (C1 to C6) alkyl, (C1 to C6) alkenyl, (C1 to C6) alkynyl, (C1 to C6) alkoxy, cyano, (C3 to C10) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, (C2 to C9) heteroaryl, —(CH2)nNR11aR11b, —(CH2)nC(O)R12, —(CH2)nC(O)NR11aR11b, —(CH2)nS(O)mR12, —(CH2)nS(O)mNR11aR11b, —(CH2)nNR11aS(O)mR12, —(CH2)nC(O)OR7, —(CH2)nC(O)NR11aR11b, —(CH2)nOC(O)R12, —(CH2)nNR11aC(O)R12 or —(CH2)nNR11aC(O)NR11aR11b;

R11a and R11b are each independently H, (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl;

each R12 is independently (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl;

each m is independently 1 or 2; and

each n is independently 0, 1, 2, 3, or 4.

One aspect of this embodiment is a compound according to Formula (I), as described above, or a salt thereof, wherein R1 is (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C6 to C14) aryl, or (C2 to C9) cycloheteroalkyl, wherein said (C1 to C6) alkyl, (C3 to CO cycloalkyl, (C6 to C14) aryl, or (C2 to C9) cycloheteroalkyl is optionally substituted with at least one R6 group.

A further aspect of this embodiment is a compound according to Formula (I), as described above, or a salt thereof, wherein R2 is (C2 to C9) heteroaryl optionally substituted with at least one R6 group.

A further aspect of this embodiment is a compound according to Formula (I), as described above, or a salt thereof, wherein R3 is hydrogen.

A further aspect of this embodiment is a compound according to Formula (I), as described above, or a salt thereof, wherein R4 is hydrogen.

A further aspect of this embodiment is a compound according to Formula (I), as described above, or a salt thereof, wherein R is hydrogen.

A further aspect of this embodiment is a compound according to Formula (I), as described above, or a salt thereof, wherein R5 is hydrogen.

A further aspect of this embodiment is a compound according to Formula (I), as described above, or a salt thereof, wherein R5 is methyl.

A further aspect of this embodiment is a compound according to Formula (I), as described above, or a salt thereof, wherein each R6 is independently —OH, halogen, CF3, —(CH2)nNR8aR8b, (C1 to C6) alkyl, (C1 to C6) alkoxy, (C6 to C14) aryl, —(CH2)nC(O)R9, —(CH2)nC(O)OR7, or —(CH2)nC(O)NR8aR8b, wherein each of the said (C1 to C6) alkyl or (C6 to C14) aryl is optionally substituted with at least one R10 group.

A further aspect of this embodiment is a compound according to Formula (I), as described above, or a salt thereof, wherein each R7 is independently (C1 to C6) alkyl optionally substituted with at least one R10 group.

A further aspect of this embodiment is a compound according to Formula (I), as described above, or a salt thereof, wherein R8a and R8b are each independently H or (C1 to C6) alkyl optionally substituted with at least one R10 group.

A further aspect of this embodiment is a compound according to Formula (I), as described above, or a salt thereof, wherein each R9 is independently (C1 to C6) alkyl optionally substituted with at least one R10 group.

A further aspect of this embodiment is a compound according to Formula (I), as described above, or a salt thereof, wherein each R19 is independently —OH, CF3, cyano, (C6 to C14) aryl, or —(CH2)nNR11aR11b.

A further aspect of this embodiment is a compound according to Formula (I), as described above, or a salt thereof, wherein R, R3 and R4 are hydrogen and R2 is (C2 to C9) heteroaryl optionally substituted with at least one R6 group.

A further aspect of this embodiment is a compound according to Formula (I), as described above, or a salt thereof, wherein R, R3 and R4 are hydrogen and R5 is methyl.

A further aspect of this embodiment is a compound according to Formula (I), as described above, or a salt thereof, wherein R, R3, R4 and R5 are hydrogen.

A further aspect of this embodiment is a compound according to Formula (I), as described above, or a salt thereof, wherein R, R3 and R4 are hydrogen and R1 is (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C6 to C14) aryl, or (C2 to C9) cycloheteroalkyl, wherein said (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C6 to C14) aryl, or (C2 to C9) cycloheteroalkyl is optionally substituted with at least one R6 group.

A further aspect of this embodiment is a compound according to Formula (I), as described above, or a salt thereof, wherein R, R3 and R4 are hydrogen, R2 is (C2 to C9) heteroaryl optionally substituted with at least one R6 group and R5 is hydrogen or methyl.

A further aspect of this embodiment is a compound according to Formula (I), as described above, or a salt thereof, wherein R, R3 and R4 are hydrogen, R2 is (C2 to C9) heteroaryl optionally substituted with at least one R6 group, R5 is hydrogen or methyl, and R1 is (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C6 to C14) aryl, or (C2 to C9) cycloheteroalkyl, wherein said (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C6 to C14) aryl, or (C2 to C9) cycloheteroalkyl is optionally substituted with at least one R6 group.

A further aspect of this embodiment is a compound according to Formula (I), as described above, or a salt thereof, wherein R1 is (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C6 to C14) aryl, or (C2 to C9) cycloheteroalkyl, wherein said (C1 to C6) alkyl, (C3 to CO cycloalkyl, (C6 to C14) aryl, or (C2 to C9) cycloheteroalkyl is optionally substituted with at least one R6 group; R, R3 and R4 are hydrogen; R2 is (C2 to C9) heteroaryl optionally substituted with at least one R6 group; R5 is hydrogen or methyl; each R6 is independently —OH, halogen, CF3, —(CH2)nNR8aR8b, (C1 to C6) alkyl, (C1 to C6) alkoxy, of the said (C1 to C6) alkyl or (C6 to C14) aryl is optionally substituted with at least one R10 group; each R7 is independently (C1 to C6) alkyl optionally substituted with at least one R10 group; R8a and R8b are each independently H or (C1 to C6) alkyl optionally substituted with at least one R10 group; each R9 is independently (C1 to C6) alkyl optionally substituted with at least one R10 group; each R10 is independently —OH, CF3, cyano, (C6 to C14) aryl, or —(CH2)nNR11aR11b; and R11a and R11b are each independently H or (C1 to C6) alkyl.

A further aspect of this embodiment is a compound according to Formula (I),

wherein:

R1 is H, (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C6 to C14) aryl, (C2 to C9) cycloheteroalkyl, or (C2 to C9) heteroaryl, wherein each said (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C6 to C14) aryl, (C2 to C9) cycloheteroalkyl, and (C2 to C9) heteroaryl is optionally substituted with at least one R6 group;

R2 is H, —(CH2)nC(O)OR7, —(CH2)nC(O)N(R8aR8b), (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C6 to C14) aryl, (C2 to C9) cycloheteroalkyl, or (C2 to C9) heteroaryl, wherein each said (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C6 to C14) aryl, (C2 to C9) cycloheteroalkyl and (C2 to C9) heteroaryl is optionally substituted with at least one R6 group;

R3 is H or (C1 to C3) alkyl;

R and R4 are independently H, halo, cyano or (C1 to C6) alkyl;

R5 is H, or (C1 to C6) alkyl optionally substituted with at least one R6 group;

each R6 is independently —OH, halogen, CF3, —(CH2)nNR8aR8b, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C1 to C6) alkoxy, cyano, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, (C2 to C9) heteroaryl, —(CH2)nC(O)R9, —(CH2)nS(O)mR9, —(CH2)nS(O)mNR8aR8b, —(CH2)nNR8aS(O)mR9, —(CH2)nC(O)OR7, —(CH2)nC(O)NR8aR8b, —(CH2)nOC(O)R9, —(CH2)nNR8aC(O)R9 or —(CH2)nNR8aC(O)NR8aR8b, wherein each said (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C1 to C6) alkoxy, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, and (C2 to C9) heteroaryl is optionally substituted with at least one R10 group;

each R7 is independently H, or (C1 to C6) alkyl optionally substituted with at least one R10 group;

R8a and R8b are each independently H, (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl wherein each said (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, and (C6 to C14) aryl is optionally substituted with at least one R10 group;

each R9 is independently (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl wherein each said (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, and (C6 to C14) aryl is optionally substituted with at least one R10 group;

each R10 is independently —OH, halogen, CF3, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C1 to C6) alkoxy, cyano, (C3 to C10) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, (C2 to C9) heteroaryl, —(CH2)nNR11aR11b, —(CH2)nC(O)R12, —(CH2)nC(O)NR11aR11b, —(CH2)nS(O)mR12, —(CH2)nS(O)mNR11aR11b, —(CH2)nNR11aS(O)mR12, —(CH2)nOC(O)R12, —(CH2)nNR11aC(O)R12 or —(CH2)nNR11aC(O)NR11aR11b;

R11a and R11b are each independently H, (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl;

each R12 is independently (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl;

each m is independently 1 or 2; and

each n is independently 0, 1, 2, 3, or 4; or

a pharmaceutically acceptable salt thereof.

A further aspect of this embodiment is a compound according to Formula (I), wherein:

R1 is (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C6 to C14) aryl, (C2 to C9) cycloheteroalkyl, or (C2 to C9) heteroaryl, wherein each said (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C6 to C14) aryl, (C2 to C9) cycloheteroalkyl, and (C2 to C9) heteroaryl is optionally substituted with at least one R6 group;

R2 is (C2 to C9) heteroaryl or (C6 to C14) aryl, each of which is optionally substituted with at least one R6 group;

R, R3 and R4 are H;

R5 is H, or (C1 to C6) alkyl optionally substituted with at least one R6 group;

each R6 is independently —OH, halogen, CF3, —(CH2)nNR8aR8b, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C1 to C6) alkoxy, cyano, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, (C2 to C9) heteroaryl, —(CH2)nC(O)R9, —(CH2)nS(O)mR9, —(CH2)nS(O)mNR8aR8b, —(CH2)nNR8aS(O)mR9, —(CH2)nC(O)OR7, —(CH2)nC(O)NR8aR8b, —(CH2)nOC(O)R9, —(CH2)nNR8aC(O)R9 or —(CH2)nNR8aC(O)NR8aR8b, wherein each said (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C1 to C6) alkoxy, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, and (C2 to C9) heteroaryl is optionally substituted with at least one R10 group;

each R7 is independently H, or (C1 to C6) alkyl optionally substituted with at least one R10 group;

R8a and R8b are each independently H, (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl wherein each said (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, and (C6 to C14) aryl is optionally substituted with at least one R10 group;

each R9 is independently (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl wherein each said (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, and (C6 to C14) aryl is optionally substituted with at least one R10 group;

each R10 is independently —OH, halogen, CF3, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C1 to C6) alkoxy, cyano, (C3 to C10) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, (C2 to C9) heteroaryl, —(CH2)nNR11aR11b, —(CH2)nC(O)R12, —(CH2)nC(O)NR11aR11b, —(CH2)nS(O)mR12, —(CH2)nS(O)mNR11aR11b, —(CH2)nNR11aS(O)mR12, —(CH2)nOC(O)R12, —(CH2)nNR11aC(O)R12 or —(CH2)nNR11aC(O)NR11aR11b;

R11a and R11b are each independently H, (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl;

each R12 is independently (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl;

each m is independently 1 or 2; and

each n is independently 0, 1, 2, 3, or 4; or

a pharmaceutically acceptable salt thereof.

A further aspect of this embodiment is a compound according to Formula (I), wherein:

R1 is (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C6 to C14) aryl, (C2 to C9) cycloheteroalkyl, or (C2 to C9) heteroaryl, wherein each said (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C6 to C14) aryl, (C2 to C9) cycloheteroalkyl, and (C2 to C9) heteroaryl is optionally substituted with at least one R6 group;

R2 is (C6 to C14) aryl, quinolinyl, pyridyl, pyrimidinyl, pyrazolyl, indolyl, pyrazolopyridinyl, or indazolyl, each of which is optionally substituted with at least one R6 group;

R, R3 and R4 are H;

R5 is H, or (C1 to C6) alkyl optionally substituted with at least one R6 group;

each R6 is independently —OH, halogen, CF3, —(CH2)nNR8aR8b, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C1 to C6) alkoxy, cyano, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, (C2 to C9) heteroaryl, —(CH2)nC(O)R9, —(CH2)nS(O)mR9, —(CH2)nS(O)mNR8aR8b, —(CH2)nNR8aS(O)mR9, —(CH2)nC(O)OR7, —(CH2)nC(O)NR8aR8b, —(CH2)nOC(O)R9, —(CH2)nNR8aC(O)R9 or —(CH2)nNR8aC(O)NR8aR8b, wherein each said (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C1 to C6) alkoxy, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, and (C2 to C9) heteroaryl is optionally substituted with at least one R10 group;

each R7 is independently H, or (C1 to C6) alkyl optionally substituted with at least one R10 group;

R8a and R8b are each independently H, (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl wherein each said (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, and (C6 to C14) aryl is optionally substituted with at least one R10 group;

each R9 is independently (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl wherein each said (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, and (C6 to C14) aryl is optionally substituted with at least one R10 group;

each R10 is independently —OH, halogen, CF3, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C1 to C6) alkoxy, cyano, (C3 to C10) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, (C2 to C9) heteroaryl, —(CH2)nNR11aR11b, —(CH2)nC(O)R12, —(CH2)nC(O)NR11aR11b, —(CH2)nS(O)mR12, —(CH2)nS(O)mNR11aR11b, —(CH2)nNR11aS(O)mR12, —(CH2)nOC(O)R12, —(CH2)nNR11aC(O)R12 or —(CH2)nNR11aC(O)NR11aR11b;

R11a and R11b are each independently H, (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl;

each R12 is independently (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl;

each m is independently 1 or 2; and

each n is independently 0, 1, 2, 3, or 4; or

a pharmaceutically acceptable salt thereof.

A further aspect of this embodiment is a compound according to Formula (I), wherein:

R1 is (C6 to C14) aryl optionally substituted with at least one R6 group;

R2 is (C2 to C9) heteroaryl or (C6 to C14) aryl, each of which is optionally substituted with at least one R6 group;

R, R3 and R4 are H;

R5 is H, or (C1 to C6) alkyl optionally substituted with at least one R6 group;

each R6 is independently —OH, halogen, CF3, —(CH2)nNR8aR8b, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C1 to C6) alkoxy, cyano, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, (C2 to C9) heteroaryl, —(CH2)nC(O)R9, —(CH2)nS(O)mR9, —(CH2)nS(O)mNR8aR8b, —(CH2)nNR8aS(O)mR9, —(CH2)nC(O)OR7, —(CH2)nC(O)NR8aR8b, —(CH2)nOC(O)R9, —(CH2)nNR8aC(O)R9 or —(CH2)nNR8aC(O)NR8aR8b, wherein each said (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C1 to C6) alkoxy, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, and (C2 to C9) heteroaryl is optionally substituted with at least one R10 group;

each R7 is independently H, or (C1 to C6) alkyl optionally substituted with at least one R10 group;

R8a and R8b are each independently H, (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl wherein each said (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, and (C6 to C14) aryl is optionally substituted with at least one R10 group;

each R9 is independently (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl wherein each said (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, and (C6 to C14) aryl is optionally substituted with at least one R10 group;

each R10 is independently —OH, halogen, CF3, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C1 to C6) alkoxy, cyano, (C3 to C10) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, (C2 to C9) heteroaryl, —(CH2)nNR11aR11b, —(CH2)nC(O)R12, —(CH2)nC(O)NR11aR11b, —(CH2)nS(O)mR12, —(CH2)nS(O)mNR11aR11b, —(CH2)nNR11aS(O)mR12, —(CH2)nOC(O)R12, —(CH2)nNR11aC(O)R12 or —(CH2)nNR11aC(O)NR11aR11b;

R11a and R11b are each independently H, (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl;

each R12 is independently (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl;

each m is independently 1 or 2; and

each n is independently 0, 1, 2, 3, or 4; or

a pharmaceutically acceptable salt thereof.

A further aspect of this embodiment is a compound according to Formula (I), wherein:

R1 is (C6 to C14) aryl optionally substituted with at least one R6 group;

R2 is (C6 to C14) aryl, quinolinyl, pyridyl, pyrimidinyl, pyrazolyl, indolyl, pyrazolopyridinyl, or indazolyl, each of which is optionally substituted with at least one R6 group;

R, R3 and R4 are H;

R5 is H, or (C1 to C6) alkyl optionally substituted with at least one R6 group;

each R6 is independently —OH, halogen, CF3, —(CH2)nNR8aR8b, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C1 to C6) alkoxy, cyano, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, (C2 to C9) heteroaryl, —(CH2)nC(O)R9, —(CH2)nS(O)mR9, —(CH2)nS(O)mNR8aR8b, —(CH2)nNR8aS(O)mR9, —(CH2)nC(O)OR7, —(CH2)nC(O)NR8aR8b, —(CH2)nOC(O)R9, —(CH2)nNR8aC(O)R9 or —(CH2)nNR8aC(O)NR8aR8b, wherein each said (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C1 to C6) alkoxy, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, and (C2 to C9) heteroaryl is optionally substituted with at least one R10 group;

each R7 is independently H, or (C1 to C6) alkyl optionally substituted with at least one R10 group;

R8a and R8b are each independently H, (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl wherein each said (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, and (C6 to C14) aryl is optionally substituted with at least one R10 group;

each R9 is independently (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl wherein each said (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, and (C6 to C14) aryl is optionally substituted with at least one R10 group;

each R10 is independently —OH, halogen, CF3, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C1 to C6) alkoxy, cyano, (C3 to C10) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, (C2 to C9) heteroaryl, —(CH2)nNR11aR11b, —(CH2)nC(O)R12, —(CH2)nC(O)NR11aR11b, —(CH2)nS(O)mR12, —(CH2)nS(O)mNR11aR11b, —(CH2)nNR11aS(O)mR12, —(CH2)nOC(O)R12, —(CH2)nNR11aC(O)R12 or —(CH2)nNR11aC(O)NR11aR11b;

R11a and R11b are each independently H, (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl;

each R12 is independently (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl;

each m is independently 1 or 2; and

each n is independently 0, 1, 2, 3, or 4; or

a pharmaceutically acceptable salt thereof.

A further aspect of this embodiment is a compound according to Formula (I), wherein:

R1 is (C2 to C9) cycloheteroalkyl, optionally substituted with at least one R6 group;

R2 is (C2 to C9) heteroaryl or (C6 to C14) aryl, each of which is optionally substituted with at least one R6 group;

R, R3 and R4 are H;

R5 is H, or (C1 to C6) alkyl optionally substituted with at least one R6 group;

each R6 is independently —OH, halogen, CF3, —(CH2)nNR8aR8b, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C1 to C6) alkoxy, cyano, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, (C2 to C9) heteroaryl, —(CH2)nC(O)R9, —(CH2)nS(O)mR9, —(CH2)nS(O)mNR8aR8b, —(CH2)nNR8aS(O)mR9, —(CH2)nC(O)OR7, —(CH2)nC(O)NR8aR8b, —(CH2)nOC(O)R9, —(CH2)nNR8aC(O)R9 or —(CH2)nNR8aC(O)NR8aR8b, wherein each said (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C1 to C6) alkoxy, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, and (C2 to C9) heteroaryl is optionally substituted with at least one R10 group;

each R7 is independently H, or (C1 to C6) alkyl optionally substituted with at least one R10 group;

R8a and R8b are each independently H, (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl wherein each said (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, and (C6 to C14) aryl is optionally substituted with at least one R10 group;

each R9 is independently (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl wherein each said (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, and (C6 to C14) aryl is optionally substituted with at least one R10 group;

each R10 is independently —OH, halogen, CF3, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C1 to C6) alkoxy, cyano, (C3 to C10) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, (C2 to C9) heteroaryl, —(CH2)nNR11aR11b, —(CH2)nC(O)R12, —(CH2)nC(O)NR11aR11b, —(CH2)nS(O)mR12, —(CH2)nS(O)mNR11aR11b, —(CH2)nNR11aS(O)mR12, —(CH2)nOC(O)R12, —(CH2)nNR11aC(O)R12 or —(CH2)nNR11aC(O)NR11aR11b;

R11a and R11b are each independently H, (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl;

each R12 is independently (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl;

each m is independently 1 or 2; and

each n is independently 0, 1, 2, 3, or 4; or

a pharmaceutically acceptable salt thereof.

A further aspect of this embodiment is a compound according to Formula (I), wherein:

R1 is (C2 to C9) cycloheteroalkyl, optionally substituted with at least one R6 group;

R2 is (C6 to C14) aryl, quinolinyl, pyridyl, pyrimidinyl, pyrazolyl, indolyl, pyrazolopyridinyl, or indazolyl, each of which is optionally substituted with at least one R6 group;

R, R3 and R4 are H;

R5 is H, or (C1 to C6) alkyl optionally substituted with at least one R6 group;

each R6 is independently —OH, halogen, CF3, —(CH2)nNR8aR8b, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C1 to C6) alkoxy, cyano, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, (C2 to C9) heteroaryl, —(CH2)nC(O)R9, —(CH2)nS(O)mR9, —(CH2)nS(O)mNR8aR8b, —(CH2)nNR8aS(O)mR9, —(CH2)nC(O)OR7, —(CH2)nC(O)NR8aR8b, —(CH2)nOC(O)R9, —(CH2)nNR8aC(O)R9 or —(CH2)nNR8aC(O)NR8aR8b, wherein each said (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C1 to C6) alkoxy, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, and (C2 to C9) heteroaryl is optionally substituted with at least one R10 group;

each R7 is independently H, or (C1 to C6) alkyl optionally substituted with at least one R10 group;

R8a and R8b are each independently H, (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl wherein each said (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, and (C6 to C14) aryl is optionally substituted with at least one R10 group;

each R9 is independently (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl wherein each said (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, and (C6 to C14) aryl is optionally substituted with at least one R10 group;

each R10 is independently —OH, halogen, CF3, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C1 to C6) alkoxy, cyano, (C3 to C10) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, (C2 to C9) heteroaryl, —(CH2)nNR11aR11b, —(CH2)nC(O)R12, —(CH2)nC(O)NR11aR11b, —(CH2)nS(O)mR12, —(CH2)nS(O)mNR11aR11b, —(CH2)nNR11aS(O)mR12, —(CH2)nOC(O)R12, —(CH2)nNR11aC(O)R12 or —(CH2)nNR11aC(O)NR11aR11b;

R11a and R11b are each independently H, (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl;

each R12 is independently (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl;

each m is independently 1 or 2; and

each n is independently 0, 1, 2, 3, or 4; or

a pharmaceutically acceptable salt thereof.

A further aspect of this embodiment is a compound according to Formula (I), wherein:

R1 is piperidinyl, optionally substituted with at least one R6 group;

R2 is (C6 to C14) aryl, quinolinyl, pyridyl, pyrimidinyl, pyrazolyl, indolyl, pyrazolopyridinyl, or indazolyl, each of which is optionally substituted with at least one R6 group;

R, R3 and R4 are H;

R5 is H, or (C1 to C6) alkyl optionally substituted with at least one R6 group;

each R6 is independently —OH, halogen, CF3, —(CH2)nNR8aR8b, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C1 to C6) alkoxy, cyano, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, (C2 to C9) heteroaryl, —(CH2)nC(O)R9, —(CH2)nS(O)mR9, —(CH2)nS(O)mNR8aR8b, —(CH2)nNR8aS(O)mR9, —(CH2)nC(O)OR7, —(CH2)nC(O)NR8aR8b, —(CH2)nOC(O)R9, —(CH2)nNR8aC(O)R9 or —(CH2)nNR8aC(O)NR8aR8b, wherein each said (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C1 to C6) alkoxy, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, and (C2 to C9) heteroaryl is optionally substituted with at least one R16 group;

each R7 is independently H, or (C1 to C6) alkyl optionally substituted with at least one R10 group;

R8a and R8b are each independently H, (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl wherein each said (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, and (C6 to C14) aryl is optionally substituted with at least one R10 group;

each R9 is independently (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl wherein each said (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, and (C6 to C14) aryl is optionally substituted with at least one R10 group;

each R10 is independently —OH, halogen, CF3, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C1 to C6) alkoxy, cyano, (C3 to C10) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, (C2 to C9) heteroaryl, —(CH2)nNR11aR11b, —(CH2)nC(O)R12, —(CH2)nC(O)NR11aR11b, —(CH2)nS(O)mR12, —(OH2)nS(O)mNR11aR11b, —(CH2)nNR11aS(O)mR12, —(CH2)nOC(O)R12, —(CH2)nNR11aC(O)R12 or —(CH2)nNR11aC(O)NR11aR11b;

R11a and R11b are each independently H, (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl;

each R12 is independently (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl;

each m is independently 1 or 2; and

each n is independently 0, 1, 2, 3, or 4; or

a pharmaceutically acceptable salt thereof.

A further aspect of this embodiment is a compound according to Formula (I), wherein:

R1 is piperidinyl, optionally substituted with at least one R6 group;

R2 is (C6 to C14) aryl, quinolinyl, pyridyl, pyrimidinyl, pyrazolyl, indolyl, pyrazolopyridinyl, or indazolyl, each of which is optionally substituted with at least one R6 group;

R, R3 and R4 are H;

R5 is H or —CH3;

each R6 is independently —OH, halogen, CF3, —(CH2)nNR8aR8b, (C1 to C6) alkyl, (C1 to C6) alkoxy, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, (C2 to C9) heteroaryl, —(CH2)nC(O)R9, —(OH2)nS(O)mNR8aR8b, or —(CH2)nNR8aC(O)NR8aR8b, wherein each said (C1 to C6) alkyl, (C1 to C6) alkoxy, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, and (C2 to C9) heteroaryl is optionally substituted with at least one R19 group;

R8a and R8b are each independently H, (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl wherein each said (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, and (C6 to C14) aryl is optionally substituted with at least one R19 group;

each R9 is independently (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl wherein each said (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, and (C6 to C14) aryl is optionally substituted with at least one R19 group;

each R10 is independently —OH, halogen, CF3, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C1 to C6) alkoxy, cyano, (C3 to C10) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, (C2 to C9) heteroaryl, —(CH2)nNR11aR11b, —(CH2)nC(O)R12, —(CH2)nC(O)NR11aR11b, —(CH2)nS(O)mR12, —(CH2)nS(O)mNR11aR11b, —(CH2)nNR11aS(O)mR12, —(CH2)nOC(O)R12, —(CH2)nNR11aC(O)R12 or —(CH2)nNR11aC(O)NR11aR11b;

R11a and R11b are each independently H, (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl;

each R12 is independently (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl;

each m is independently 1 or 2; and

each n is independently 0, 1, 2, 3, or 4; or

a pharmaceutically acceptable salt thereof.

A further aspect of this embodiment is a compound according to Formula (I), wherein:

R1 is (C3 to C8) cycloalkyl, optionally substituted with at least one R6 group;

R2 is (C2 to C9) heteroaryl or (C6 to C14) aryl, each of which is optionally substituted with at least one R6 group;

R, R3 and R4 are H;

R5 is H, or (C1 to C6) alkyl optionally substituted with at least one R6 group;

each R6 is independently —OH, halogen, CF3, —(CH2)nNR8aR8b, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C1 to C6) alkoxy, cyano, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, (C2 to C9) heteroaryl, —(CH2)nC(O)R9, —(CH2)nS(O)mR9, —(CH2)nS(O)mNR8aR8b, —(CH2)nNR8aS(O)mR9, —(CH2)nC(O)OR7, —(CH2)nC(O)NR8aR8b, —(CH2)nOC(O)R9, —(CH2)nNR8aC(O)R9 or —(CH2)nNR8aC(O)NR8aR8b, wherein each said (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C1 to C6) alkoxy, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, and (C2 to C9) heteroaryl is optionally substituted with at least one R10 group;

each R7 is independently H, or (C1 to C6) alkyl optionally substituted with at least one R10 group;

R8a and R8b are each independently H, (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl wherein each said (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, and (C6 to C14) aryl is optionally substituted with at least one R10 group;

each R9 is independently (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl wherein each said (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, and (C6 to C14) aryl is optionally substituted with at least one R10 group;

each R10 is independently —OH, halogen, CF3, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C1 to C6) alkoxy, cyano, (C3 to C10) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, (C2 to C9) heteroaryl, —(CH2)nNR11aR11b, —(CH2)nC(O)R12, —(CH2)nC(O)NR11aR11b, —(CH2)nS(O)mR12, —(CH2)nS(O)mNR11aR11b, —(CH2)nNR11aS(O)mR12, —(CH2)nOC(O)R12, —(CH2)nNR11aC(O)R12 or —(CH2)nNR11aC(O)NR11aR11b;

R11a and R11b are each independently H, (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl;

each R12 is independently (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl;

each m is independently 1 or 2; and

each n is independently 0, 1, 2, 3, or 4; or

a pharmaceutically acceptable salt thereof.

A further aspect of this embodiment is a compound according to Formula (I), wherein:

R1 is (C3 to C8) cycloalkyl, optionally substituted with at least one R6 group;

R2 is (C6 to C14) aryl, quinolinyl, pyridyl, pyrimidinyl, pyrazolyl, indolyl, pyrazolopyridinyl, or indazolyl, each of which is optionally substituted with at least one R6 group;

R, R3 and R4 are H;

R5 is H, or (C1 to C6) alkyl optionally substituted with at least one R6 group;

each R6 is independently —OH, halogen, CF3, —(CH2)nNR8aR8b, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C1 to C6) alkoxy, cyano, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, (C2 to C9) heteroaryl, —(CH2)nC(O)R9, —(CH2)nS(O)mR9, —(CH2)nS(O)mNR8aR8b, —(CH2)nNR8aS(O)mR9, —(CH2)nC(O)OR7, —(CH2)nC(O)NR8aR8b, —(CH2)nOC(O)R9, —(CH2)nNR8aC(O)R9 or —(CH2)nNR8aC(O)NR8aR8b, wherein each said (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C1 to C6) alkoxy, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, and (C2 to C9) heteroaryl is optionally substituted with at least one R10 group;

each R7 is independently H, or (C1 to C6) alkyl optionally substituted with at least one R10 group;

R8a and R8b are each independently H, (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl wherein each said (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, and (C6 to C14) aryl is optionally substituted with at least one R10 group;

each R9 is independently (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl wherein each said (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, and (C6 to C14) aryl is optionally substituted with at least one R10 group;

each R10 is independently —OH, halogen, CF3, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C1 to C6) alkoxy, cyano, (C3 to C10) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, (C2 to C9) heteroaryl, —(CH2)nNR11aR11b, —(CH2)nC(O)R12, —(CH2)nC(O)NR11aR11b, —(CH2)nS(O)mR12, —(CH2)nS(O)mNR11aR11b, —(CH2)nNR11aS(O)mR12, —(CH2)nOC(O)R12, —(CH2)nNR11aC(O)R12 or —(CH2)nNR11aC(O)NR11aR11b;

R11a and R11b are each independently H, (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl;

each R12 is independently (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl;

each m is independently 1 or 2; and

each n is independently 0, 1, 2, 3, or 4; or

a pharmaceutically acceptable salt thereof.

A further aspect of this embodiment is a compound according to Formula (I), wherein R1 is cyclohexyl optionally substituted with at least one R6 group, or a pharmaceutically acceptable salt thereof.

A further aspect of this embodiment is a compound according to Formula (I), wherein:

R1 is (C1 to C6) alkyl, optionally substituted with at least one R6 group;

R2 is (C2 to C9) heteroaryl or (C6 to C14) aryl, each of which is optionally substituted with at least one R6 group;

R, R3 and R4 are H;

R5 is H, or (C1 to C6) alkyl optionally substituted with at least one R6 group;

each R6 is independently —OH, halogen, CF3, —(CH2)nNR8aR8b, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C1 to C6) alkoxy, cyano, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, (C2 to C9) heteroaryl, —(CH2)nC(O)R9, —(CH2)nS(O)mR9, —(CH2)nS(O)mNR8aR8b, —(CH2)nNR8aS(O)mR9, —(CH2)nC(O)OR7, —(CH2)nC(O)NR8aR8b, —(CH2)nOC(O)R9, —(CH2)nNR8aC(O)R9 or —(CH2)nNR8aC(O)NR8aR8b, wherein each said (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C1 to C6) alkoxy, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, and (C2 to C9) heteroaryl is optionally substituted with at least one R10 group;

each R7 is independently H, or (C1 to C6) alkyl optionally substituted with at least one R10 group;

R8a and R8b are each independently H, (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl wherein each said (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, and (C6 to C14) aryl is optionally substituted with at least one R10 group;

each R9 is independently (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl wherein each said (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, and (C6 to C14) aryl is optionally substituted with at least one R19 group;

each R19 is independently —OH, halogen, CF3, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C1 to C6) alkoxy, cyano, (C3 to C10) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, (C2 to C9) heteroaryl, —(CH2)nNR11aR11b, —(CH2)nC(O)R12, —(CH2)nC(O)NR11aR11b, —(CH2)nS(O)mR12, —(CH2)nS(O)mNR11aR11b, —(CH2)nNR11aS(O)mR12, —(CH2)nOC(O)R12, —(CH2)nNR11aC(O)R12 or —(CH2)nNR11aC(O)NR11aR11b;

R11a and R11b are each independently H, (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl;

each R12 is independently (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl;

each m is independently 1 or 2; and

each n is independently 0, 1, 2, 3, or 4; or

a pharmaceutically acceptable salt thereof.

A further aspect of this embodiment is a compound according to Formula (I), wherein R1 is (C1 to C6) alkyl, optionally substituted with —OH, or a pharmaceutically acceptable salt thereof.

A further aspect of this embodiment is a compound according to Formula (I), wherein R1 is 2-hydroxy-1-methylethyl, or a pharmaceutically acceptable salt thereof.

A further aspect of this embodiment is a compound according to Formula (I), wherein:

R1 is (C1 to C6) alkyl, optionally substituted with at least one R6 group;

R2 is (C6 to C14) aryl, quinolinyl, pyridyl, pyrimidinyl, pyrazolyl, indolyl, pyrazolopyridinyl, or indazolyl, each of which is optionally substituted with at least one R6 group;

R, R3 and R4 are H;

R5 is H, or (C1 to C6) alkyl optionally substituted with at least one R6 group;

each R6 is independently —OH, halogen, CF3, —(CH2)nNR8aR8b, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C1 to C6) alkoxy, cyano, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, (C2 to C9) heteroaryl, —(CH2)nC(O)R9, —(CH2)nS(O)mR9, —(CH2)nS(O)mNR8aR8b, —(CH2)nNR8aS(O)mR9, —(CH2)nC(O)OR7, —(CH2)nC(O)NR8aR8b, —(CH2)nOC(O)R9, —(CH2)nNR8aC(O)R9 or —(CH2)nNR8aC(O)NR8aR8b, wherein each said (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C1 to C6) alkoxy, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, and (C2 to C9) heteroaryl is optionally substituted with at least one R10 group;

each R7 is independently H, or (C1 to C6) alkyl optionally substituted with at least one R10 group;

R8a and R8b are each independently H, (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl wherein each said (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, and (C6 to C14) aryl is optionally substituted with at least one R10 group;

each R9 is independently (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, or (C6 to C14) aryl wherein each said (C1 to C6) alkyl, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, and (C6 to C14) aryl is optionally substituted with at least one R10 group;